tbuckley/cabot-search huggingface dataset:
A randomized study using combination of statin and ascorbic acid for prevention of contrast-induced nephropathy (NCT03391830)
Authors: A. Hashem, M. Laymon, M. Elgamal, A.M. Lashin, A.E. Abolazm, M. Bahy, M. Ramez, H. Refaie, Y. Osman
Journal: European Urology (2022)
Hydrogel microcapsules containing engineered bacteria for sustained production and release of protein drugs
Authors: Chunli Han, Xinyu Zhang, Gaoju Pang, Yingying Zhang, Huizhuo Pan, Lianyue Li, Meihui Cui, Baona Liu, Ruru Kang, Xin Xue, Tao Sun, Jing Liu, Jin Chang, Peiqi Zhao, Hanjie Wang
Journal: Biomaterials (2022)
The position of urethrovesical anastomosis after robotic radical prostatectomy assessed by MRI predicts early functional recovery: A cohort analyses from a randomized clinical trial
Authors: M. Triquell Llaurado, L. Regis, A. Salazar, J. Planas, A. Celma, M. Cuadras, S. Roche, R. Mast, J. Morote, E. Trilla
Journal: European Urology (2022)
Comprehensive molecular characterization of Chinese patients with biliary tract cancers.
Authors: Daren Liu, Dan Ye, Jinhong Wu, Yangyang Yu, Lele Zhao, Mingzhe Xiao, Chuang Qi
Journal: Journal of Clinical Oncology (2022)

e16153 Background: Biliary tract cancers are clinically heterogenous with poor prognosis. The traditional location-based classification of biliary tract cancers is helpful while the boundary between subtypes is still ambiguous. We hereby analyzed the comprehensive molecular characterizations across different types among biliary tract cancers and further to identify the similarities and differences and help with the individualized treatment. Methods: Tumor tissue samples from 219 Chinese biliary tract cancer patients were profiled by next generation sequencing with a 539 gene panel by the Illumina NovaSeq 6000 (Illumina, San Diego, CA, USA) sequencing platform. Tumor mutation burden (TMB) was calculated by counting all nonsynonymous mutations per megabase of coding sequences. Results: A total of 219 biliary tract cancer (BTC) patients with a median age of 61 years(range 29–83 years) were enrolled, including 147 gallbladder cancer (GBC), 51 intrahepatic cholangiocarcinoma (iCCA) and 21 hilar cholangiocarcinoma (hCCA). These samples consisted of 93 males and 126 females. The most frequent mutated genes were TP53 (73%), ARID1A (18%), MUC16 (16%) in GBC, TP53 (57%), KRAS (35%), ARID1A (16%), PIK3CA (16%) in iCCA, TP53 (48%), KRAS (29%), ARID1A (14%) in hCCA. The mutation of BCORL1 (P = 0.002) and IRF4 (P = 0.006) had a significant association with age. The median TMB was 4.26 mutations/Mb in GBC, 2.94 mutations/Mb in iCCA and 2.84 mutations/Mb in hCCA. Patients with ATM mutation and FAT1 mutation had a significant higher TMB level (P＜0.001). The mutations of common target genes in different types of BTC were analyzed. The mutations of IDH1, target gene of Ivosidenib, were detected in 4 (1.83%) patients (1 in GBC, 2 in iCCA, 1in hCCA). The mutations of FGFR1/2/3/4, target gene of Erdafitinib, were detected in 10 (4.57%) patients (8 in GBC, 2 in iCCA, 0 in hCCA). The most frequently affected pathways in GBC, iCCA and hCCA were TP53 (78.2%, 60.8%, 47.6%), RTK-RAS (52.4%, 64.7%, 47.6%), PIK3 (34%, 39.2%, 33.3%). Conclusions: The genomic profiling and molecular characterization among different anatomic locations could support the exploration of tumor development mechanism and provide theoretic basis for developing diagnosis and treatment methods for biliary tract cancers patients.
Comparative single-cell RNA-sequencing profiling of BMP4-treated primary glioma cultures reveals therapeutic markers
Authors: Iris S C Verploegh, Andrea Conidi, Rutger W W Brouwer, Hayri E Balcioglu, Panagiotis Karras, Samira Makhzami, Anne Korporaal, Jean-Christophe Marine, Martine Lamfers, Wilfred F J Van IJcken, Sieger Leenstra, Danny Huylebroeck
Journal: Neuro-Oncology (2022)

Abstract Background Glioblastoma (GBM) is the most aggressive primary brain tumor. Its cellular composition is very heterogeneous, with cells exhibiting stem-cell characteristics (GSCs) that co-determine therapy resistance and tumor recurrence. Bone Morphogenetic Protein (BMP)-4 promotes astroglial and suppresses oligodendrocyte differentiation in GSCs, processes associated with superior patient prognosis. We characterized variability in cell viability of patient-derived GBM cultures in response to BMP4 and, based on single-cell transcriptome profiling, propose predictive positive and early-response markers for sensitivity to BMP4. Methods Cell viability was assessed in 17 BMP4-treated patient-derived GBM cultures. In two cultures, one highly-sensitive to BMP4 (high therapeutic efficacy) and one with low-sensitivity, response to treatment with BMP4 was characterized. We applied single-cell RNA-sequencing, analyzed the relative abundance of cell clusters, searched for and identified the aforementioned two marker types, and validated these results in all 17 cultures. Results High variation in cell viability was observed after treatment with BMP4. In three cultures with highest sensitivity for BMP4, a substantial new cell subpopulation formed. These cells displayed decreased cell proliferation and increased apoptosis. Neuronal differentiation was reduced most in cultures with little sensitivity for BMP4. OLIG1/2 levels were found predictive for high sensitivity to BMP4. Activation of ribosomal translation (RPL27A, RPS27) was up-regulated within one day in cultures that were very sensitive to BMP4. Conclusion The changes in composition of patient-derived GBM cultures obtained after treatment with BMP4 correlate with treatment efficacy. OLIG1/2 expression can predict this efficacy, and upregulation of RPL27A and RPS27 are useful early-response markers.
Baseline endogenous corticosteroid as a biomarker for predicting response to immune checkpoint blockade in patients with metastatic cancer.
Authors: Jun Wang, Yu Cui, Yaping Guan, Beibei Yin, Qi Xie
Journal: Journal of Clinical Oncology (2022)

e14588 Background: Previous studies indicate that exogenous use of corticosteroids affects immune checkpoint inhibitor (ICI) efficacy comparing patients receiving corticosteroids versus no corticosteroids. However, there is a paucity of clinical data evaluating the direct effect of endogenous corticosteroids on ICI efficacy for cancer patients with immune checkpoint blockade. Methods: We retrospectively reviewed patients with advanced cancer who were treated with PD-1 inhibitor alone or combination therapy in a single center between December 2019 and January 2022. Serum corticosteroid levels (8:00 AM) were routinely measured before ICI treatment. The effects of serum corticosteroids on objective response rate (ORR), progression‐free survival (PFS), and overall survival (OS) were analyzed. Propensity score matching (PSM) analysis was performed to match the characteristics of the high and low serum corticosteroid groups. Results: A total of 144 patients were included in this retrospective cohort study. The median age was 62.5 years and 71.5% was male. Overall, ORR was 20.1%, and median OS and PFS were 22.2 and 4.9 months, respectively. Patients with low corticosteroid levels (n = 64) had a significantly improved ORR compared to those with high corticosteroid levels (n = 80) (34.4% vs 8.8%; p &lt; 0.001). The increased corticosteroid level was significantly associated with reduced OS ( p &lt; 0.001) and PFS ( p = 0.025) for all patients and those with non-small cell lung cancer regarding OS ( p = 0.004). Moreover, statistically significant differences regarding OS ( p = 0.017) were also detected after PSM. In a multivariable model, the corticosteroid level was identified as an independent indicator for predicting OS ( p = 0.001) and PFS ( p = 0.006). Conclusions: Endogenous corticosteroid can predict efficacy and prognosis for advanced cancer patients with immune checkpoint blockade. Baseline evaluation of baseline corticosteroids should be considered before ICI initiation. Further prospective clinical trials designed to validate the predictive role of endogenous corticosteroid are warranted.
Risks assessment of significant renal function deterioration after partial nephrectomy and call for reconsidering the imperative setting
Authors: U. Anceschi, A. Brassetti, G. Tuderti, R. Mastroianni, A.M. Bove, M.C. Ferriero, L. Misuraca, A. Minervini, A. Mari, A.A. Grosso, U. Capitanio, A. Larcher, F. Montorsi, R. Autorino, A. Veccia, C. Fiori, D. Amparore, F. Porpiglia, D. Eun, J. Lee, I. Deerwesh, C. Sundaram, J. Steward, M. Gallucci, G. Simone
Journal: European Urology (2022)
A signature for pan-cancer prognosis based on neutrophil extracellular traps
Authors: Yi Zhang, Liping Guo, Qichen Dai, Bingqing Shang, Ting Xiao, Xuebing Di, Kaitai Zhang, Lin Feng, Jianzhong Shou, Yipeng Wang
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Neutrophil extracellular traps (NETs) were originally thought to be formed by neutrophils to trap invading microorganisms as a defense mechanism. Increasing studies have shown that NETs play a pivotal role in tumor progression and diffusion. In this case, transcriptome analysis provides an opportunity to unearth the association between NETs and clinical outcomes of patients with pan-cancer. Methods The transcriptome sequencing data of The Cancer Genome Atlas pan-cancer primary focus was obtained from UCSC Xena, and a 19-gene NETs score was then constructed using the Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression model based on the expression levels of 69 NETs initial biomarkers we collected from multistudies. In addition, multiple datasets covering multiple cancer types from other databases were collected and used to validate the signature. Gene ontology enrichment analyses were used to annotate the functions of NETs-related pathways. Immunohistochemistry (IHC) was implemented to evaluate the role of NETs-related genes in clinical patients across types of tumors, including lung adenocarcinoma (n=58), colorectal carcinoma (n=93), kidney renal clear cell carcinoma (n=90), and triple-negative breast cancer (n=80). Results The NETs score was calculated based on 19-NETs related genes according to the LASSO Cox model. The NETs score was considered a hazardous factor in most cancer types, with a higher score indicating a more adverse outcome. In addition, we found that NETs were significantly correlated to various malignant biological processes, such as the epithelial to mesenchymal transition (R=0.7444, p&lt;0.0001), angiogenesis (R=0.5369, p&lt;0.0001), and tumor cell proliferation (R=0.3835, p&lt;0.0001). Furthermore, in IHC cohorts of a variety of tumors, myeloperoxidase, a gene involved in the model and a classical delegate of NETs formation, was associated with poor clinical outcomes. Conclusions Collectively, these constitutive and complementary biomarkers represented the ability of NETs formation to predict the development of patients’ progression. Integrative transcriptome analyses plus clinical sample validation may facilitate the biomarker discovery and clinical transformation.
Impact of immune-related adverse events (irAEs) on PD-1/L1 inhibitors efficacy in advanced esophageal cancer.
Authors: Wenru Qin, Linlin Wang
Journal: Journal of Clinical Oncology (2022)

4061 Background: The recent development of Immune checkpoint inhibitors (ICIs) has improved treatment outcomes for patients with esophageal cancer, although it may initiate autoimmune-related disorders in some patients. Across disease sites, patients who experience irAEs while on therapy with anti-PD-1 and anti-PD-L1 antibodies have been documented to experience improved outcomes as measured by overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). Methods: We reviewed the medical records and the following characteristics of patients were collected: age, gender, Eastern Cooperative Oncology Group performance status (ECOG PS), stage, histology, history of surgery, metastatic sites, therapy line, presence of target lesion according to the response evaluation criteria in solid tumors (RECIST) version 1.1, LDH level before initiating ICIs treatment. We divided the patients treated with ICIs into two groups based on occurrence of irAEs. We compared the efficacy between the irAE - and irAE + groups. Results: There were total 295 patients. Of all the patients, 143 patients (50.2%) suffered from irAEs. The median patient age was 60 years (range, 36–84). Baseline characteristics including gender, ECOG PS, tumor location, history of surgery, histology, number of organs with metastases, site of metastases, therapy line, history of drinking, history of smoking between patients with or without irAE were not significantly different. The most frequent irAEs were Anemia(71/295, 24.07%), Pneumonitis (55/295, 18.64%), Cardiovascular toxicities (35/295, 11.86%). There were no grade 5 adverse events related to immunotherapy. Objective response was observed in 92 patients (31.19%), 54 of the 143 patients with irAEs had objective response (37.76%) in contrast with 38 of the 152 cases without irAEs (25.00%). Median PFS in patients with irAEs was 10.27 months and 6.2 months in those without irAEs (p&lt;0.001). Median OS in patients with irAEs was 15.4 months and 9.2 months in those without irAEs(p&lt;0.001).Multivariate analyses identified an ECOG PS ≥2, cycles ≤8, and without irAEs as independent poor prognostic factors (p=0.003, p &lt;0.001 and p=0.011). Multivariate analysis demonstrated that ECOG PS ≥2, Therapy line≥22nd,without radiation and absence of irAEs were associated with a poor overall survival(p=0.022, p=0.006, p. &lt;0.001 and p=0.002). Multivariable analysis also revealed that Cycles&gt;8, Radiation and Antiangiogenic therapy were positively associated with occurrence of irAEs(p&lt;0.001, p=0.002, p=0.025). Conclusions: In advanced esophageal cancer treated with PD-1/L1 inhibitors., patients with irAEs showed a markedly improved efficacy over patients without irAEs.
Nurse AMIE: Addressing symptoms in rural patients with advanced cancer.
Authors: Cristina I. Truica, Kathryn Schmitz, Shawna Doerksen, William Calo, Nicole Lynn Stout, Ming Wang, Eugene Lengerich, Jennifer Moss, David J. Vanness
Journal: Journal of Clinical Oncology (2022)

TPS12148 Background: Prior research has shown that monitoring symptoms in advanced cancer patients may provide a survival benefit. Monitoring is a labor-intensive process that requires nursing staff response and visiting a medical office. This may be more challenging in rural areas, given staffing challenges and distances traveled for care. Lower density of supportive care services has been documented in rural as compared to urban settings in Pennsylvania and West Virginia. We have developed a computer tablet-based supportive care program, called Nurse AMIE, and are investigating its use in symptom management among cancer survivors. Our hypothesis is that a tablet-based supportive care program can improve overall survival of advanced cancer patients in rural Pennsylvania and West Virginia. Methods: This randomized controlled trial will recruit 344 patients residing in a rural county or zip code (RUCC 4-9 or RUCA 4-10) in Pennsylvania or West Virginia, who receive treatment for stage III-IV cancer, are 18 years or older, ECOG 0-3, are fluent in written and spoken English, have sufficient vision/hearing to interact with a computer tablet and staff, and have a clinician-defined life expectancy of 6 months or more. Exclusion criteria: patients on active treatment or behavioral or supportive care trials, or with medical or psychiatric conditions that would impair ability to test study hypotheses. Patients will be randomized on a 1:1 basis to receive either Nurse AMIE or a binder with written supportive care materials. Intervention participants will be asked to log into Nurse AMIE daily, where they will interact with a nurse avatar and answer symptom questions (focusing on sleep, fatigue, pain, and distress). They will receive an empathic response to symptoms and be offered evidence based, guideline concordant self-care interventions to address symptoms (including exercise, nutrition, guided meditation, cognitive behavioral therapy videos, and soothing music). Once weekly, patients will answer 21 questions from the Pro-CTCAE survey. All symptom data will be loaded into a dashboard reviewed daily by study staff. Pain or distress scores of 7+ (out of 10) will be communicated to the care team through the EMR. The trial is powered to detect a 19% difference in overall survival at 2 years follow-up (based on Denis et al JAMA 2019). Secondary outcomes include incidence of chemotherapy toxicities, patient reported outcomes, and cost effectiveness. Enrollment is anticipated to start in March 2022. A community advisory board of 12 cancer patients and stakeholders meet on a quarterly basis to provide feedback on study activities (e.g., usability testing, adaptations, overall implementation) and ensure the project responds to the needs and preferences of rural cancer patients in Pennsylvania and West Virginia. NIH R01-CA254659. Clinical trial information: NCT05221606.
Faulty autolysosome acidification in Alzheimer’s disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques
Authors: Ju-Hyun Lee, Dun-Sheng Yang, Chris N. Goulbourne, Eunju Im, Philip Stavrides, Anna Pensalfini, Han Chan, Cedric Bouchet-Marquis, Cynthia Bleiwas, Martin J. Berg, Chunfeng Huo, James Peddy, Monika Pawlik, Efrat Levy, Mala Rao, Mathias Staufenbiel, Ralph A. Nixon
Journal: Nature Neuroscience (2022)

Autophagy is markedly impaired in Alzheimer's disease (AD). Here we reveal unique autophagy dysregulation within neurons in five AD mouse models in vivo and identify its basis using a neuron-specific transgenic mRFP-eGFP-LC3 probe of autophagy and pH, multiplex confocal imaging and correlative light electron microscopy. Autolysosome acidification declines in neurons well before extracellular amyloid deposition, associated with markedly lowered vATPase activity and build-up of Aβ/APP-βCTF selectively within enlarged de-acidified autolysosomes. In more compromised yet still intact neurons, profuse Aβ-positive autophagic vacuoles (AVs) pack into large membrane blebs forming flower-like perikaryal rosettes. This unique pattern, termed PANTHOS (poisonous anthos (flower)), is also present in AD brains. Additional AVs coalesce into peri-nuclear networks of membrane tubules where fibrillar β-amyloid accumulates intraluminally. Lysosomal membrane permeabilization, cathepsin release and lysosomal cell death ensue, accompanied by microglial invasion. Quantitative analyses confirm that individual neurons exhibiting PANTHOS are the principal source of senile plaques in amyloid precursor protein AD models.
Serologic Biomarkers of Progression Toward Diagnosis of Rheumatoid Arthritis in Active Component Military Personnel
Authors: Matthew J. Loza, Sunil Nagpal, Suzanne Cole, Renee M. Laird, Ashley Alcala, Navin L. Rao, Mark S. Riddle, Chad K. Porter
Journal: Arthritis & Rheumatology (2022)

To identify a panel of serum biomarkers that could specifically identify imminent cases of rheumatoid arthritis (RA) before diagnosis.Serum samples were collected at 4 time points from active component US military personnel, including 157 anti-citrullinated protein antibody (ACPA)-seropositive and 50 ACPA-seronegative RA subjects, 100 reactive arthritis (ReA) subjects, and 76 healthy controls. The cohorts were split into 2 phases, with samples tested on independent proteomic platforms for each phase. Classification models of RA diagnosis based on samples obtained within 6 months prior to diagnosis were developed both in univariate analyses and by multivariate random forest modeling of training sample sets and testing sample sets from each phase.Increases in serum analytes, including C-reactive protein levels, serum amyloid A, and soluble programmed cell death 1 (PD-1), were observed in seropositive RA subjects at the time point closest to diagnosis, up to several years before diagnosis. Only a small fraction of RA subjects had levels above the 95th percentile of healthy control levels until the time period within 6 months of diagnosis. For classification of RA diagnosis using samples obtained within 6 months prior to diagnosis, soluble PD-1 provided superior specificity compared to ReA cases (>89%), with a sensitivity of 48% for RA classification. An 8-analyte model provided superior sensitivity (69%), with comparable specificity relative to ReA (>82%).Our findings demonstrate that imminent RA diagnosis could be classified with high specificity, relative to healthy controls and ReA cases, using a panel of cytokines measured in serum samples collected within 6 months before actual diagnosis.
Osimertinib plus necitumumab in EGFR-mutant NSCLC: Final results from an ETCTN California Cancer Consortium phase I study.
Authors: Jonathan W. Riess, Mark D. Krailo, Sukhmani Kaur Padda, Susan G. Groshen, Heather A. Wakelee, Karen L. Reckamp, Marianna Koczywas, Zofia Piotrowska, Conor Ernst Steuer, Chul Kim, Cloud P. Paweletz, Lynette M. Sholl, Grace Heavey, Jill Kolesar, Jeffrey Moscow, Pasi A. Janne, Primo "Lucky" N. Lara, Edward M. Newman, David R. Gandara
Journal: Journal of Clinical Oncology (2022)

9014 Background: Osimertinib (Osi) is standard of care in 1 st line (1L) EGFR mut NSCLC and TKI resistant T790M pos NSCLC but acquired resistance emerges; outcomes are less robust in T790M neg , C797X pos and EGFR exon 20 insertion (ex20ins) disease. We examined Osi with the EGFR monoclonal antibody Necitumumab (Neci) in select settings of EGFR TKI resistance. Methods: Pts were accrued to 5 expansion cohorts (ExC) at recommended phase 2 dose (RP2D) of Osi 80 mg daily and Neci 800 mg D1 + D8 of q21d cycle. ExC (18 pts/cohort): A) T790M neg progressive disease (PD) on 1 st /2 nd gen TKI as last therapy, B) T790M neg PD on 1 st /2 nd gen TKI and PD on 3 rd gen TKI, C) T790M pos PD on 1 st /2 nd gen TKI and PD on 3 rd gen TKI, D) EGFR ex20ins PD on chemotherapy, E) PD on 1L osi. In ExC A-C, T790M was confirmed centrally (tissue) by ddPCR. Additional correlative studies include: tissue NGS (&gt; 400 gene panel), EGFR FISH, plasma for PK and serial EGFR ctDNA by ddPCR. Adverse events were graded (Gr) by CTCAEv5; ORR, PFS by RECIST 1.1. Primary pre-specified efficacy endpoint ≥3/18 pts responding per cohort. Results: 101 patients accrued (100 evaluable). Efficacy is summarized in the Table. Drug related Gr 3 AEs were seen in 38% of pts, mainly rash (21%). ORR among all pts was 19% (95% CI 12-28%) that varied across cohorts (Table). In ExC A-C, 69% pts had detectable EGFR activating mutations in ctDNA, with decline in mutant allele frequency (AF) on treatment in 80% and ctDNA clearance in 33%. Conclusions: Osi/Neci is feasible and tolerable at the RP2D. EGFR ctDNA was detectable at baseline in the majority of pts with decrease in AF on treatment. Osi/Neci was active in select settings of EGFR-TKI resistance, meeting its prespecified efficacy endpoint in T790M neg PD on 1 st /2 nd gen TKI as last therapy (ExC A), EGFR ex20ins post-chemo (ExC D) and PD on 1L osimertinib (ExC E). mPFS in the EGFR ex20ins cohort was within the range of current EGFR Exon 20 ins agents in development. EGFR monoclonal antibodies with osimertinib warrant further study in settings of de novo and acquired EGFR dependent resistance to EGFR-TKI. Clinical trial information: NCT02496663. [Table: see text]